Abstract

To predict the impact of liver cirrhosis on hepatic drug clearance using physiologically based pharmacokinetic (PBPK) modeling, we compared the protein abundance of various Phase I and Phase II drug metabolizing enzymes (DMEs) in S9 fractions of alcoholic (n=27) or hepatitis C (HCV, n=30) cirrhotic vs. non-cirrhotic (control) livers (n=25). The S9 total protein content was significantly lower in alcoholic or HCV cirrhotic vs. control livers (i.e., 38.3 ± 8.3, 32.3 ± 12.8 vs. 51.1 ± 20.7 mg/g liver, respectively). In general, alcoholic cirrhosis was associated with a larger decrease in the DME abundance than HCV cirrhosis. However, only the abundance of UGT1A4, ADH1A and ADH1B was significantly lower in alcoholic vs. HCV cirrhotic livers. When normalized to per gram of tissue, the abundance of nine DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, CYP1A2, ADH1A, ADH1B, AOX1 and CES1) in alcoholic cirrhosis and five DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, and CYP1A2) in HCV cirrhosis was <25% of that in control livers. The abundance of the majority of DMEs in cirrhotic livers was 25-50% of control livers. CES2 abundance was not affected by cirrhosis. Integration of UGT2B7 abundance in cirrhotic livers into the liver cirrhosis (Child Pugh C) model of Simcyp improved the prediction of zidovudine and morphine PK in subjects with Child Pugh C liver cirrhosis. These data demonstrate that protein abundance data, combined with PBPK modeling and simulation, can be a powerful tool to predict drug disposition in special populations.